EP1397128B1 - Kappa-opiatagonist für die behandlung der reizblase - Google Patents
Kappa-opiatagonist für die behandlung der reizblase Download PDFInfo
- Publication number
- EP1397128B1 EP1397128B1 EP02724228A EP02724228A EP1397128B1 EP 1397128 B1 EP1397128 B1 EP 1397128B1 EP 02724228 A EP02724228 A EP 02724228A EP 02724228 A EP02724228 A EP 02724228A EP 1397128 B1 EP1397128 B1 EP 1397128B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- bladder
- treatment
- phenyl
- methyl
- hydroxypyrrolidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 206010005052 Bladder irritation Diseases 0.000 title claims abstract description 13
- 238000011282 treatment Methods 0.000 title claims description 17
- 239000000556 agonist Substances 0.000 title description 4
- JHLHNYVMZCADTC-LOSJGSFVSA-N asimadoline Chemical compound C([C@@H](N(C)C(=O)C(C=1C=CC=CC=1)C=1C=CC=CC=1)C=1C=CC=CC=1)N1CC[C@H](O)C1 JHLHNYVMZCADTC-LOSJGSFVSA-N 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
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- 201000010099 disease Diseases 0.000 abstract description 6
- 241001465754 Metazoa Species 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 239000007928 intraperitoneal injection Substances 0.000 abstract description 2
- 239000002632 kappa opiate receptor agonist Substances 0.000 abstract description 2
- 239000002504 physiological saline solution Substances 0.000 abstract description 2
- 230000003187 abdominal effect Effects 0.000 abstract 1
- 229950002202 asimadoline Drugs 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
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- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
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- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
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- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
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- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
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- 239000009975 Urodyn Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000012084 abdominal surgery Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
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- 230000009699 differential effect Effects 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
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- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 210000002758 humerus Anatomy 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000008384 ileus Diseases 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 208000015238 neurotic disease Diseases 0.000 description 1
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- 230000003204 osmotic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 208000026533 urinary bladder disease Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
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- 235000013343 vitamin Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
Definitions
- the invention relates to the use of the drug N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or one of its pharmacologically acceptable salts for the manufacture of a medicament for the treatment of irritable bladder and associated pain.
- the active pharmaceutical ingredient N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) ethyl] -2,2-diphenyl-acetamide acts analgesic, antiinflammatory, anti-asthmatic, diuretic, anticonvulsant, neuroprotective and antitussive and, as a kappa opiate agonist, is particularly suitable for the treatment of inflammatory hyperalgesia, for the treatment of brain edema, in under-treatment conditions (hypoxia), pain, as well as for the reduction of the consequential damage of ischemia.
- N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or its pharmacologically acceptable salts for The preparation of a medicament for the treatment of inflammatory bowel disease and the associated disease symptoms, for the treatment of severe pain, especially pain in back disorders, burn injuries, sunburn and rheumatic diseases as well as for the treatment of postoperative pain as well as the ileus often occurring after abdominal surgery in the EP 0 752 246 disclosed.
- N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or any of the pharmacologically acceptable salts is also suitable for the treatment of functional gastrointestinal disorders associated with pain and / or increased or decreased perestals, in particular the Irritable Bowel Syndrome or for the treatment of non-ulcer dyspepsia, constipation, in particular opiod-induced constipation, arthritis, migraine, Psoriasis or other itchy skin disorders, dysmenorrhea and fibromylagia,
- EP 0 569 802 describes pharmaceutical preparations containing N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) ethyr] -2,2-diphenylacetamide as active ingredient.
- US 5,965,701 describes peptides which have a high selectivity for the kappa opioid receptor and can be used for the treatment of bladder diseases.
- the irritable bladder also called irritable bladder, cytalgi, cystalgia, neuralgia vesicae or bladder neurosis which at the same time relieve the pain associated with this condition and cure the condition.
- irritable bladder stands for a chronic irritation of the lower urinary tract that occurs mainly in women. Symptoms include dysuria, imperative urgency, pollakiuria, suprapubic and diffuse pain when sitting. Often there is a marked discrepancy between subjective complaints and the objective findings. The most common causes are disorders of the psycho-vegetative or endocrine system.
- the irritable bladder is to be distinguished from other diseases, such as urinary tract infections and changes in the lower humerus, diseases of adjacent pelvic organs or CNS or spinal cord diseases (eg multiple sclerosis).
- the drug substance N-methyl-N - [(1S) -1-phenyl) -2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or one of the pharmacologically acceptable salts, in particular the hydrochloride is surprisingly effective for the treatment of irritable bladder, despite the known diuretic effect of asimadolin.
- the invention therefore relates to the use of the drug N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or one of its pharmacologically acceptable salts for the preparation of medicament formulations for the treatment of the irritable bladder,
- N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or one of its pharmacologically acceptable salts can therefore be used for the preparation of pharmaceutical Preparations for the treatment of irritable bladder, used by mixing them with at least one Carrier or excipient and, if desired, with one or more other active ingredients in the appropriate dosage form brings.
- Suitable carrier substances are organic or inorganic substances which are suitable for enteral (eg oral or rectal) or parenteral administration and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides , Gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
- suppositories for parenteral administration solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants.
- the active compounds claimed according to the invention can also be lyophilized and the resulting lyophilizates z. B. be used for the preparation of injection preparations.
- the preparations indicated may be sterilized and / or contain adjuvants such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. You can, if desired, also contain one or more other active ingredients, for. B. one or more vitamins.
- N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide or one of its pharmacologically acceptable salts is disclosed in U.S. Pat the rule in analogy to other known preparations commercially available for the claimed indication, preferably in dosages between about 0.1 mg and 50 mg, in particular between 5 and 30 mg per dosage unit.
- the daily dosage is preferably between about 0.02 and 20 mg / kg, in particular 0.1 and 10 mg / kg body weight.
- the specific dose for each individual patient will depend on a variety of factors, for example, the effectiveness of the particular compound employed, age, body weight, general health, gender, diet, time and route of administration, rate of excretion, drug combination, and Severity of the particular disease to which the therapy applies. Oral administration is preferred.
- a model for measuring the influence on urinary excretion is included Lipschitz et. al., J. Pharmacol. Exp. Ther. 1943; 79: 97-110 described.
- the substance to be examined is given to rats, which were previously deprived of food overnight with free water access.
- An increased urine excretion is provoked by the simultaneous intraperitoneal injection of 100 ml / kg of physiological saline.
- the bladder was emptied by gently massaging the abdomen over the bladder. Subsequently, the rats are kept in metabolism cages in which the urine is collected over the period of 6 hours.
- N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide increases urinary output dose-dependently, with a 2-fold increase higher urine output is excreted at the dose of 100 mg / kg.
- N-methyl-N - [(1S) -1-phenyl-2 - ((3S) -3-hydroxypyrrolidin-1-yl) -ethyl] -2,2-diphenyl-acetamide increases the urinary excretion dose-dependently, already at 30 mg / kg po is excreted 5.5 times higher urine.
- Bladder performance measured in ml / cm, decreases by almost 95%.
- the emptying behavior changes greatly, the frequency of emptying increases sharply with the Picture of a frequent dribble with a draining volume reduced by about 70%.
- Behavioral observation of the animals over a period of four weeks results in a reduced repertoire of reduced frequency of general and especially social activities, while stereotypical, self-referential behaviors such as licking, scratching, scratching increase sharply.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07111669A EP1834640A3 (de) | 2001-04-05 | 2002-03-13 | Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase |
| SI200230593T SI1397128T1 (sl) | 2001-04-05 | 2002-03-13 | Kapa-opiatni agonisti za zdravljenje razdraĹľljivega mehurja |
| CY20071101231T CY1109001T1 (el) | 2001-04-05 | 2007-09-25 | Οι καππα-οπιοιδεις αγωνιστες στη θεραπεια των παθησεων της κυστης |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10116978 | 2001-04-05 | ||
| DE10116978A DE10116978A1 (de) | 2001-04-05 | 2001-04-05 | Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase |
| PCT/EP2002/002756 WO2002080905A1 (de) | 2001-04-05 | 2002-03-13 | Kappa-opiatagonisten für die behandlung von erkrankungen der blase |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP07111669A Division EP1834640A3 (de) | 2001-04-05 | 2002-03-13 | Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1397128A1 EP1397128A1 (de) | 2004-03-17 |
| EP1397128B1 true EP1397128B1 (de) | 2007-07-04 |
Family
ID=7680492
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02724228A Expired - Lifetime EP1397128B1 (de) | 2001-04-05 | 2002-03-13 | Kappa-opiatagonist für die behandlung der reizblase |
| EP07111669A Withdrawn EP1834640A3 (de) | 2001-04-05 | 2002-03-13 | Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP07111669A Withdrawn EP1834640A3 (de) | 2001-04-05 | 2002-03-13 | Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US20040157913A1 (cs) |
| EP (2) | EP1397128B1 (cs) |
| JP (1) | JP2004525165A (cs) |
| KR (1) | KR100851938B1 (cs) |
| CN (1) | CN1268332C (cs) |
| AT (1) | ATE366109T1 (cs) |
| AU (1) | AU2002254947B2 (cs) |
| BR (1) | BR0208488A (cs) |
| CA (1) | CA2443019C (cs) |
| CY (1) | CY1109001T1 (cs) |
| CZ (1) | CZ20032899A3 (cs) |
| DE (2) | DE10116978A1 (cs) |
| DK (1) | DK1397128T3 (cs) |
| ES (1) | ES2290286T3 (cs) |
| HU (1) | HUP0303910A3 (cs) |
| MX (1) | MXPA03009099A (cs) |
| MY (1) | MY136683A (cs) |
| PL (1) | PL363540A1 (cs) |
| PT (1) | PT1397128E (cs) |
| RU (1) | RU2307651C2 (cs) |
| SK (1) | SK13272003A3 (cs) |
| WO (1) | WO2002080905A1 (cs) |
| ZA (1) | ZA200308600B (cs) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10259245A1 (de) * | 2002-12-17 | 2004-07-01 | Merck Patent Gmbh | Derivate des Asimadolins mit kovalent gebundenen Säuren |
| CA2544245A1 (en) * | 2003-10-30 | 2005-05-26 | Tioga Pharmaceuticals, Inc. | Use of selective opiate receptor modulators in the treatment of neuropathy |
| CN101677997B (zh) | 2007-03-30 | 2012-05-09 | 泰奥加制药公司 | 用于治疗腹泻型和交替型肠易激综合征的κ-阿片剂激动剂 |
| WO2013142197A1 (en) * | 2012-03-19 | 2013-09-26 | Wellesley Pharmaceuticals, Llc | Extended-release formulation for reducing the frequency of urination and method of use thereof |
| US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
| US20140179727A1 (en) | 2012-12-14 | 2014-06-26 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
| US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
| CN118512453A (zh) | 2018-07-23 | 2024-08-20 | 特雷维治疗股份有限公司 | 慢性咳嗽、呼吸急促和呼吸困难的治疗 |
| WO2021142288A1 (en) | 2020-01-10 | 2021-07-15 | Trevi Therapeutics, Inc. | Methods of administering nalbuphine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6A (en) * | 1836-08-10 | Thomas Blanchard | Machine for forming end pieces of plank blocks for ships | |
| US5A (en) * | 1836-08-10 | Thomas Blanchard | Machine for mortising solid wooden shells of ships' tackle-blocks | |
| DE4215213A1 (de) * | 1992-05-09 | 1993-11-11 | Merck Patent Gmbh | Arylacetamide |
| CA2099233A1 (en) * | 1992-06-29 | 1993-12-30 | Conrad P. Dorn | Morpholine and thiomorpholine tachykinin receptor antagonists |
| DE19523502A1 (de) * | 1995-06-28 | 1997-01-02 | Merck Patent Gmbh | Kappa-Opiatagonisten für entzündliche Darmerkrankungen |
| DE19531464A1 (de) * | 1995-08-26 | 1997-02-27 | Merck Patent Gmbh | N-Methyl-N-[(1S-)-1-phenyl-2-((3S)-3-hydroxypyrrolidin 1-yl-)-ethyl]-2,2-diphenyl-acetamid |
| US5859043A (en) * | 1996-06-11 | 1999-01-12 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Method for maintaining kidney function during surgery or severe trauma under general anesthesia |
| US6201022B1 (en) * | 1997-03-27 | 2001-03-13 | Myorx, Inc. | Methods for treating neurotransmitter-mediated pain syndromes by topically administering an omega fatty acid |
| US5965701A (en) | 1997-12-23 | 1999-10-12 | Ferring Bv | Kappa receptor opioid peptides |
-
2001
- 2001-04-05 DE DE10116978A patent/DE10116978A1/de not_active Withdrawn
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2002
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- 2002-03-13 KR KR1020037012331A patent/KR100851938B1/ko not_active Expired - Fee Related
- 2002-03-13 AU AU2002254947A patent/AU2002254947B2/en not_active Ceased
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- 2002-03-13 EP EP02724228A patent/EP1397128B1/de not_active Expired - Lifetime
- 2002-03-13 WO PCT/EP2002/002756 patent/WO2002080905A1/de not_active Ceased
- 2002-03-13 EP EP07111669A patent/EP1834640A3/de not_active Withdrawn
- 2002-03-13 CN CNB028073983A patent/CN1268332C/zh not_active Expired - Fee Related
- 2002-03-13 MX MXPA03009099A patent/MXPA03009099A/es active IP Right Grant
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- 2002-03-13 DK DK02724228T patent/DK1397128T3/da active
- 2002-03-13 ES ES02724228T patent/ES2290286T3/es not_active Expired - Lifetime
- 2002-03-13 SK SK1327-2003A patent/SK13272003A3/sk not_active Application Discontinuation
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- 2002-03-13 RU RU2003130641/14A patent/RU2307651C2/ru active
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-
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| MXPA03009099A (es) | 2004-02-12 |
| CN1499967A (zh) | 2004-05-26 |
| PT1397128E (pt) | 2007-09-03 |
| CZ20032899A3 (cs) | 2004-06-16 |
| CY1109001T1 (el) | 2014-07-02 |
| DE50210422D1 (de) | 2007-08-16 |
| DE10116978A1 (de) | 2002-10-10 |
| EP1834640A3 (de) | 2009-12-23 |
| DK1397128T3 (da) | 2007-10-15 |
| CA2443019A1 (en) | 2002-10-17 |
| KR20040025909A (ko) | 2004-03-26 |
| HK1064036A1 (en) | 2005-01-21 |
| CA2443019C (en) | 2009-12-29 |
| MY136683A (en) | 2008-11-28 |
| AU2002254947B2 (en) | 2007-06-07 |
| ZA200308600B (en) | 2004-09-13 |
| PL363540A1 (en) | 2004-11-29 |
| SK13272003A3 (sk) | 2004-02-03 |
| ATE366109T1 (de) | 2007-07-15 |
| RU2307651C2 (ru) | 2007-10-10 |
| CN1268332C (zh) | 2006-08-09 |
| WO2002080905A1 (de) | 2002-10-17 |
| HUP0303910A2 (hu) | 2004-03-29 |
| RU2003130641A (ru) | 2005-03-10 |
| US20040157913A1 (en) | 2004-08-12 |
| EP1397128A1 (de) | 2004-03-17 |
| ES2290286T3 (es) | 2008-02-16 |
| JP2004525165A (ja) | 2004-08-19 |
| EP1834640A2 (de) | 2007-09-19 |
| HUP0303910A3 (en) | 2005-04-28 |
| KR100851938B1 (ko) | 2008-08-12 |
| BR0208488A (pt) | 2004-03-02 |
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